Central vascular access devices (CVADs) are medical devices that are implanted into a patient's vascular system and are typically used in applications which provide a means for repeated access to a patient's vascular system. Applications for CVADs are varied and include, for example, intravenous feeding, intravenous drug delivery, and extracorporeal protocols. Specific applications include chemotherapy treatments, intensive antibiotic treatment, prolonged IV feeding, and extracorporeal blood treatment protocols, such as hemodialysis, hemofiltration, and apheresis.
CVADs having an exterior component (located outside the skin of a patient) are convenient to use and may be used safely by skilled practitioners who use sterile cannulas to access the CVAD and who provide sufficient maintenance in the form of regular flushing and dressing changes. However, an added risk of infection exists due to the presence of the exterior component. Specifically, the external component may serve as a route of exposure to airborne contaminants such as bacteria.
Total implantation venous access devices, also referred to herein as TIVADs are a variety of vascular access devices that are implanted into a patient's vascular system but that do not have any exterior components. The entire device is implanted under the patient's skin. TIVADs have become used more routinely, where possible, as opposed to other central vascular access devices (CVADs) having an exterior component. An example of a TIVAD is an arterial-venous (A-V) port used in accessing the circulatory system, for example, in performing dialysis treatments. The port is accessed through the skin by percutaneous placement of a HUBER needle or other connecting tube. An example of a conventional port is shown in FIG. 1. The A-V port, referred to generally as reference numeral 2, includes a lumen catheter 4 coupled to one or more reservoir access port 6 via a catheter connector 8. The catheter 4 resides in the vein. The port 6 includes an impenetrable housing 10 defining a reservoir for fluids. The housing 10 includes an opening for receiving a plastic or metal disk having a septum 12 in the center. The septum 12 is a needle penetrable elastometric material and acts as a portal to the reservoir. Further examples of commercial ports include those disclosed in U.S. Pat. No. 5,399,168, or VAXGEL implantable ports (available from Boston Scientific, Natick, Mass.).
TIVADs such as ports require less maintenance that other CVADs. For example, a properly functioning port may require flushing only once a month. Furthermore, no external dressing is necessary for such ports. An advantage of using TIVADs over other CVADs is the reduced risk of infection arising from the protective skin barrier which prevents any possible exposure to airborne contamination. A further advantage of TIVADs over CVADs generally is greater patient acceptance.
Risks associated with the use of CVADs include local complications such as thrombosis and thrombophlebitis, as well as systemic complications including embolisms, pulmonary edema and bloodstream infections. Although the risk of infection is reduced in TIVADs as compared to other CVADs, it is still possible for a patient to experience an infection at the port, particularly the area where the port is accessed.
The average time a TIVAD-type A-V port remains useful for A-V access is about two years. During these two years, infection will develop in around 20% of patients, and often leads to removal of the port. In this case, A-V access has to be reestablished. Often, this means finding another site for A-V access and waiting a period of time of up to three weeks before a normal hemodialysis schedule can be resumed.
Infection of the A-V port has been recorded as a major cause of death in patients receiving dialysis treatments. There are principally three ways in which an infection can be introduced during A-V access set up or the hemodialysis procedure itself. First, bacteria can be implanted with the A-V access device itself during a break in aseptic technique. Second, bacteria may already be present on the surface of the device. Third, bacteria can be transmitted from external sources, such as central venous catheters and needles. The entry site for infection is typically the puncture site.
The course of treatment for infections related to CVADs depends upon the type of medical device, the condition of the patient, and the identity of the bacteria causing the infection. The most common infectious agents are: staphylococcus aureus, pseudomonas aeruginosa, and staphylococcus epidermis. These agents have been identified in over 75% of all reported vascular infections. Both staphylococcus aureus and pseudomonas aeruginosa, show high virulence and can lead to clinical signs of infection early in the post-operative period (less than four months). It is this virulence that leads to septicemia and is one main factor in the high mortality rates. Staphylococcus epidermis is described as a low virulence type of bacterium. It is late occurring, which means it can present clinical signs of infection up to five years post-operative. This type of bacterium has been shown to be responsible for up to 60% of all vascular graft infections.
Vascular port infections are difficult to treat with the standard course of oral antibiotics. Accordingly, infections of this type often require total graft excision, debridement of surrounding tissue, and revascularization through an uninfected route. It would be advantageous for implantable medical devices, such as ports, to be provided with a mechanism to deliver a therapeutic agent to address such infections, at the site of infection.
Generally, it is known that certain design parameters are critical to proper delivery of therapeutic agents. Typically, they are: (1) delivering the agent to the target tissue; (2) supplying the agent in the correct temporal pattern for a predetermined period of time; and (3) fabricating a delivery system that provides the desired spatial and temporal pattern. Controlled or sustained release delivery systems are intended to manipulate these parameters to achieve the aforementioned advantages when compared to conventional dosing. A typical drug concentration versus time profile for a conventional parenteral or oral dosage form (A) and an idealized sustained drug delivery system (B) might look as shown in FIG. 2.
A disadvantage of presently available methods for providing therapeutic agents on medical device substrates is the lack of a means to control the rate of release of the therapeutic agent. For example, in conventional biodegradable polymers, a steady state rate or sustained release of drug occurs, based on, inter alia, the rate of degradation of the polymer. Accordingly, there is no control over the time or rate of delivery of the therapeutic agent. It is possible, using these systems, for the therapeutic agent to be depleted by the time it is needed by the patent. Thus, the patient is dosed with therapeutic agent even if there is no infection. Furthermore, an active infection may require a larger dose than is delivered by sustained release of the therapeutic (i.e. anti-microbial) agent.
It would therefore be advantageous, for an implanted medical device such as a CVAD, in particular a TIVAD, to provide variable drug release, so as to increase the dose of the therapeutic agent when necessary to address an active infection.